Cardiovascular diseases account for 12 million deaths annually worldwide and myocardial infraction (MI) is a leading cause of morbidity and mortality. Cardiac rupture, ventricular arrhythmia and heart failure are common causes of morbidity and mortality following MI. Cardiac rupture refers to a rupture of the left ventricle of the heart, generally following an acute myocardial infarction. Left untreated, the condition usually is fatal immediately or within a few days depending on the extent of the rupture. It is believed that such rupture occurs in approximately 10% of patients with fatal acute myocardial infarction [38]. Myocardial rupture causes 25,000 deaths a year in the United States alone and is the second most common cause of the death after an acute myocardial infarction.
Clinical studies have shown that incidence of cardiac rupture occurs in about 4-10% of all patients admitted with an acute MI, but is responsible for 12% of in-hospital mortality after thrombolytic therapy [1, 17, 28, 38]. Postmortem examinations showed cardiac ruptures in 31-65% of patients who died of acute MI [18, 27]. Thus understanding the underlying mechanisms that lead to cardiac rupture will aid in the development of drugs that will decrease mortality following MI.
The myocardial extracellular matrix (ECM) plays an important role in maintaining the integrity and function of the heart [9]. The major constituents of the myocardial ECM are the fibrillar collagens composed of the tensile collagen I (about 80%), which is crucial for coordinating contraction, and collagen III (about 10%) which provides elasticity [3, 9]. Fibrillar collagens are synthesized as precursor peptides that are proteolytically cleaved at the amino- and carboxy-terminals before being inserted into the nascent fibrils [3]. One of the major inducers of collagen expression and synthesis by fibroblasts is the transforming growth factor-beta (TGF-β) [3]. Remodeling of the ECM is mediated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) [2]. An imbalance between the activities of MMPs and TIMPs can impair infarct healing and result in cardiac rupture [16, 30, 39].
TIMPs appear to be a family of 4 homologous proteins all of which are expressed in the heart [9]. Unique among the TIMPs, TIMP-3 (metalloproteinase inhibitor 3) is ECM bound, a potent inhibitor of all known MMPs, and is expressed at high levels in the healthy heart. However, in the diseased heart, TIMP-3 expression is reduced in association with maladaptive myocardial remodeling in patients with congestive heart failure [7]. Furthermore, loss of TIMP-3 expression in aged mice triggers progressive myocardial remodeling and dysfunction even in the absence of imposed stresses or injuries [8]. In humans, the TIMP3 gene that encodes for the metalloproteinase inhibitor 3 appears to be located on chromosome 22.
Maladaptive left ventricular remodeling has been consistently associated with a poor prognosis in patients after MI and in patients with chronic heart failure [39].
Following MI, cardiac fibroblasts initially repopulate the injured area through chemotaxis. This is followed by increased proliferation and differentiation into myofibroblasts, and formation of a granulated scar [3]. Subsequently, remodeling of the ECM occurs and ultimately leads to the formation of a mature scar tissue which is composed of collagen, fibroblasts, newly formed capillaries, and macrophages [4, 31]. TIMP-3 is a potent inducer of cardiac fibroblast proliferation [23]. Furthermore, a recent study showed that incidence of pericardial bleeding, indicative of cardiac rupture, was increased in TIMP-3−/− mice post-MI [32], suggesting a potential role of TIMP-3 in infarct scar healing.
Early post-infarct adaptation of the heart could be beneficial and promote survival, however, with deleterious long-term haemodynamic consequences. Long term progressive remodeling of the left ventricle with increases in the ventricular cavity size can occur up to 2 years post-infarct and it may be associated with increased cardiovascular death, while minor reductions in remodeling can be associated with decreased heart failure and cardiovascular death [53].
Reperfusion therapy, fibrinolytic therapy, primary percutaneous coronary intervention and currently available pharmacological treatment such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta blockers, aldosterone antagonists, to name a few, have been shown to limit, to some extent, cardiac dysfunction and adverse left ventricular (LV) remodeling in patients with acute MI. Current European guidelines support the strategy of starting with ACEI and beta-blockers early after MI [53]. Despite these therapeutic approaches, maladaptive LV remodeling is still observed in a substantial proportion of these patients [39]. Most drugs used to prevent LV remodeling after MI also impair infarct healing and collagen synthesis. Therefore, drugs such as ACEI, ARBs, aldosterone antagonists may prolong the time window of vulnerability for adverse LV remodeling during post-MI healing [53].
Accordingly, new methods and compounds, which can synergistically co-operate with the current available therapies, are still needed to prevent or minimize the time window of vulnerability for adverse cardiac remodeling
There is, therefore, a need in the art for compounds and efficient therapeutic methods for the inhibition of maladaptive cardiac remodeling, cardiac rupture and other diseases, conditions, complications and/or disorders associated with heart disease.
Recent studies have shown that TIMP-3 inhibits epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling via inhibition of MMP activity in the heart [15]. EGF has been implicated in inhibiting collagen synthesis [6, 18, 19] and the expression of TGF-β1 [36] which is a potent inducer of collagen synthesis [3, 20, 21].
Activation of EGFR is known to inhibit collagen synthesis during acute MI, which is critical to infarct scar healing during the early stage of MI. Until now, no method or drug has been designed to target the EGFR function as a treatment of MI.